Schizophrenia is a chronic, severe, and disabling brain disorder which causes significant social or occupational dysfunction, such as long-term unemployment, poverty and homelessness. The previous studies indicate abnormal cerebral bioenergetics associated with schizophrenia by measurements of the steady-state concentrations of high energy phosphate-containing compounds (HEP: PCr and ATP) and in-organic phosphate (Pi) using 1H or 31P MRS. Mitochondrial energy production system is of enormous importance for neuron function, synapses and neuroplasticity which is associated with learning, memory, as well as with adaptive changes in emotional, cognitive and sensorimotor function. Therein detecting mitochondrial energy metabolic rate would provide the crucial information for better understanding the altered function of the neuron. Despite intensive research, the mechanism of abnormal cerebral energy metabolism linked to the etiology and pathophysiology of schizophrenia has remained elusive. Our recent studies in anesthetic rats' brains demonstrate that measurements of cerebral energy metabolic rates catalyzed by the creatine kinase (CK) and ATPase enzymes by 31P magnetization transfer (MT) spectroscopy provide more sensitive and quantitative measures of brain bioenergetics and its changes associated with brain activity changes under physiological or pathological condition as compared to the measurements of the steady-state HEP concentration. Thus, we believe that dynamically assessing the chemical reaction activities of creatine kinase (CK) and ATPase enzymes in schizophrenic patients would provide direct and more sensitive power meter to reflect mitochondria dysfunction associated with schizophrenia. However, it is extremely difficult to measure CK and ATPase reaction activities in human psychiatric patients by the conventional 31P MT spectroscopy. The progress in this development has been hampered for several decades due to many methodological challenges. Therefore, the current studies aim to develop a novel 31P MT methodology to noninvasively and rapidly detect abnormal bioenergetics in schizophrenia with the increased spatial resolution, higher sensitivity and reliability. The established MR methodology and preliminary findings about schizophrenia would provide an important framework which addresses the questions regarding to specific pathophysiology associated with schizophrenia and is essential for potential medical diagnosis and drug developments. PUBLIC HEALTH RELEVANCE: Schizophrenia is a chronic, severe, and disabling brain disorder that causes significant social or occupational dysfunction. The current project aims to develop a novel magnetic resonance methodology to noninvasively and rapidly detect abnormal bioenergetics in schizophrenia. It should provide an important framework to address questions regarding the specific pathophysiology associated with schizophrenia.